Vaccines have been used for many years to protect humans and animals against a wide variety of infectious diseases. Such conventional vaccines consist of attenuated pathogens (for example, polio virus), killed pathogens (for example, Bordetella pertussis) or immunogenic components of the pathogen (for example, diphtheria toxoid). Some antigens are highly immunogenic and are capable alone of eliciting protective immune responses. Other antigens, however, fail to induce a protective immune response or induce only a weak immune response. This low immunogenicity can be significantly improved if the antigens are co-administered with adjuvants. Adjuvants enhance the immunogenicity of an antigen but are not necessarily immunogenic themselves. Adjuvants may act by retaining the antigen locally near the site of administration to produce a depot effect facilitating a slow, sustained release of antigen to cells of the immune system. Adjuvants can also attract cells of the immune system to an antigen depot and stimulate such cells to elicit immune responses. Adjuvants have been identified that enhance the immune response to antigens delivered parenterally. Some of these adjuvants are toxic, however, and can cause undesirable side-effects, making them unsuitable for use in humans and many animals. Indeed, only aluminum hydroxide and aluminum phosphate are routinely used as adjuvants in human and veterinary vaccines. However, even these adjuvants are not suitable for use with all antigens and can also cause irritation at the site of injection. There is a clear need to develop novel adjuvants which are safe and efficacious for enhancing the immunogenicity of antigens.
Immunization can also be achieved by the delivery of antigens to mucosal surfaces, such as by ingestion of the antigen. Thus, it is known that the ingestion of antigens by animals can result in the appearance of antigen-specific secretory IgA antibodies in intestinal, bronchial or nasal washings and other external secretions. For example, studies with human volunteers have shown that oral administration of influenza vaccine is effective at inducing secretory anti-influenza antibodies in nasal secretions and substances have been identified which might be useful as adjuvants for such ingested vaccines. However, most of these adjuvants are relatively poor in terms of improving immune responses to ingested antigens. Currently, some of these adjuvants have been determined to be safe and efficacious in enhancing immune responses in humans and animals to antigens that are administered via the orogastrointestinal, nasopharyngeal-respiratory and genital tracts or in the ocular orbits. However, administration of antigens via these routes is generally ineffective in eliciting an immune response. The inability to immunize at the mucosal surface is generally believed to be due to:
the destruction of the antigen or a reduction in its immunogenicity in the acidic and/or enzymatically hostile environments created by secretions produced at the mucosal epithelium; PA1 the dilution of the antigen to a concentration that is below that required to induce immune responses; PA1 the carriage of antigen from the body in discharges originating at the mucosal epithelium; and the lack of suitable adjuvants which remain active at the mucosal epithelium. PA1 a solid core comprising a polysaccharide and a proteinaceous material; and PA1 an organometallic polymer bonded to the core. Such particulate carrier generally has a particle size from about 10 nm to about 50 .mu.m, preferably from about 1 to about 10 .mu.m. PA1 (a) forming an aqueous composition comprising a dissolved polysaccharide and a dispersed or dissolved proteinaceous material; PA1 (b) forming an emulsion in which the aqueous composition is the dispersed phase; PA1 (c) forming from the emulsion a particulate carrier comprising a core of said polysaccharide and proteinaceous material having bonded thereto an organometallic polymer; and PA1 (d) collecting the particulate carrier so formed. PA1 (a) ease and safety of microparticle manufacture; PA1 (b) biocompatability and safety of the microparticles; PA1 (c) improved immunogenicity of antigens presented to cells of the immune system by the microparticles; PA1 (d) ease of storage and administration; and PA1 (e) fabrication conditions that do not adversely affect the biological activity of proteinaceous or other material.
Clearly, there is a need to identify powerful adjuvants which are safe and efficacious for use at the mucosal epithelium in the orogastrointestinal, nasopharyngeal-respiratory and urogenital tracts and in the ocular orbits and at other mucosal sites.
Sensitive antigens may be entrapped to protect them against destruction, reduction in immunogenicity or dilution. The antigen can be coated with a single wall of polymeric material or can be dispersed within a monolithic matrix. Thus, U.S. Pat. No. 5,151,264 describes a particulate carrier of a phospholipid/glycolipid/polysaccharide nature that has been termed Bio Vecteurs Supra Moleculaires (BVSM). The particulate carriers are intended to transport a variety of molecules having biological activity in one of the layers thereof. However, U.S. Pat. No. 5,151,264 does not describe particulate carriers containing antigens for immunization and particularly does not describe particulate carriers for immunization via the orogastrointestinal, nasopharyngeal-respiratory and urogenital tracts and in the ocular orbits or other mucosal sites.
U.S. Pat. No. 5,075,109 describes encapsulation of the antigens trinitrophenylated keyhole limpet hemocyanin and staphylococcal enterotoxin B in 50:50 poly (DL-lactide-co-glycolide). Other polymers for encapsulation are suggested, such as poly(glycolide), poly(DL-lactide-co-glycolide), copolyoxalates, polycaprolactone, poly(lactide-co-caprolactone), poly(esteramides), polyorthoesters and poly(8-hydroxybutyric acid), and polyanhydrides. The encapsulated antigen was administered to mice via gastric intubation and resulted in the appearance of significant antigen-specific IgA antibodies in saliva and gut secretions and in sera. As stated in this patent, in contrast, the oral administration of the same amount of unencapsulated antigen was ineffective at inducing specific antibodies of any isotype in any of the fluids tested. Poly(DL-lactide-co-glycolide) microcapsules were also used to administer antigen by parenteral injection.
Published PCT application WO 91/06282 describes a delivery vehicle comprising a plurality of bioadhesive microspheres and antigenic vaccine ingredients. The microspheres being of starch, gelatin, dextran, collagen or albumin. This delivery vehicle is particularly intended for the uptake of vaccine across the nasal mucosa. The delivery vehicle may additionally contain an absorption enhancer. The antigens are typically encapsulated within protective polymeric materials.